Radiopharmaceuticals For Nuclear Cardiology Studies. Mark Soffing, PharmD, MBA, MS, RPh, BCNP

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1 Radiopharmaceuticals For Nuclear Cardiology Studies Mark Soffing, PharmD, MBA, MS, RPh, BCNP

2 Objectives Understand basics and advantages of myocardial imaging Describe isotopes and radiopharmaceuticals available in cardiac imaging Describe methods of pharmacological stress Review some technical aspects of protocols

3 Kit Preparation Aseptic technique ALWAYS alcohol swabs, fresh syringes & saline vials Assay the Tc99m activity Do not exceed package insert recommendations Add the Tc99m activity Sufficient volume to dissolve contents of vial Agitate gently and let stand Adjust concentration by adding saline

4 Radiochemical Purity Related to bonding of isotope to reagent For Tc99m, it represents the reduction of TcO +7 4 to TcO +4 4 and bonding of TcO +4 4 to carrier. Verification by means of chromatography methods generally designed around the physical properties of both the radiopharmaceutical and impurities that form. For Tc99m, there may be bound Tc99m, or free and hydrolyzed/reduced impurities.

5 Sestamibi QC Procedure Ethanol: Top: Tagged radiopharmaceutical Bottom: Free Tc-99m, hydrolyzed reduced Tc-99m % tagged Tc-99m = (top counts)/(bottom counts + top counts) x 100

6 Heart Functions as a Pump Heart pumps blood around the vascular system in two circuits (right atrium pumps blood to the lung in the pulmonary circulation, and the left atrium pumps blood to the whole body in the systemic circulation) Main parameter for function is the Cardiac Output (Index) l/min (/m 2 ) Each beat the ventricle pumps a volume of blood called the stroke volume (EDV-ESV) Ejection fraction: % of blood expelled by the ventricle in each beat EDV-ESV EDV

7 Evaluation of Cardiac Function Non-invasive tests: Exercise physiology Echocardiography (very beneficial for measuring the ejection fraction) GBPS, First pass studies, Gated SPECT Invasive Cardiac catheterization (angiopathy)

8 Radiopharmaceuticals In Nuclear Cardiac Imaging Procedures Myocardial perfusion SPECT Thallium-201 Tc-99m Sestamibi Tc-99m Tetrofosmin Cardiac function - Tc-99m Pertechnetate Myocardial metabolism - F-18 Deoxyglucose PET Rubidium-82 N-13 ammonia

9 Regulatory Food For Thought: Pharmaceutical Outsourcing and JCAHO

10 RadioNuclide Cardiac Angiography (RNCA) Multi-Gated Cardiac Blood Pool Imaging (MUGA) Dynamic imaging of the cardiac blood pool (cavity) to evaluate ventricular size, wall motion and ejection fraction Accurate and reproducible measurement of LVEF (left ventricular ejection fraction) most suitable for follow up (after chemotherapy, MI) Can be done with exercise/stress in the study of patients with CAD (coronary artery disease)

11 Gated Blood Pool Indications Patients with coronary artery disease (rest and exercise): EF response to exercise Induced wall motion abnormalities Prognosis post-mi (EF, ventricular aneurysm) Pre and post bypass surgery Patients receiving anthracycline chemotherapy (Adriamycin) to monitor cardiac toxicity because adriamycin is cardio-toxic Presurgical evaluation

12 Scintigraphic Technique Radiopharmaceuticals: Blood pool agents 99m Tc RBC: usually in vivo labeling, in vitro, or modified in vivo/vitro give better labeling Pertechnetate enters RBCs, reduced by intracellular stannous ion, and bound to hemoglobin Instrumentation: Scintillation camera with on-line acquisition ECG monitor (trigger) The patient is given 99m Tc and monitored with a gamma camera which is connected to ECG monitor.

13 Regulatory Food For Thought: Re-Infusion of Blood Products and DOH

14 MUGA Analysis Qualitative: Size and configuration of cardiac chambers: dilatation, thick wall, etc Regional wall motion: normal, hypokinetic (decreased movement), akinetic (no movement), dyskinetic (movement in the opposite direction) Quantitative: LVEF, regional EF, stroke volume Diastolic function: LV filling rate and time to peak filling rate RVEF: problem with reproducibility Phase analysis

15 Infarct-Avid Imaging Pathophysiology Necrotic tissue accumulates in phosphate compounds (bone imaging agents) due to presence of calcium deposits. This finding is useful for the diagnosis of atypical cases of myocardial infarction in which clinical, biochemical and electrocardiographic data are inconclusive.

16 99m Tc Pyrophosphate Scan Normal: no uptake in the heart (grade 0) Diagnostic value Acute myocardial infarction with atypical presentation and lab findings Right (and left) ventricular infarction Peri-operative infarction (CABG) 99m Tc PYP, 25 mci - given intravenously Image (planar & SPECT) at 3-4 hr Repeat after 3 hr if necessary

17 Myocardial Perfusion Study Assess coronary blood flow Demonstrate blood perfusing the LV myocardium Performed at rest & stress Software allows gating for EF 3D reconstruction of heart

18 Patient Preparation Continue taking cardiac meds when evaluating effectiveness of therapy Any stress procedure NPO at least 4, preferably 12 hours off beta-blocker medications Chemical stress procedure off caffeine and asthma medications for adenosine/persantine chemical stress Any rest procedure requires no patient prep Hemodynamically & clinically stable at least 48 hours

19 Thallous Cloride Thallium-201 is a potassium analog which can be detected by single photon emission computed tomography (SPECT) Uptake by myocardial cells depends on an active transport process requiring intact sarcolemmal membranes and adequate ATP stores Images are obtained at rest and 4 hours later In normal myocardium, intial uptake is high but decreases rapidly within hours

20 Technetium Tc-99m Sestamibi Technetium Tc-99m Tetrofosmin Lipophilic cationic compounds Methoxy isobutyl isonitrile Ethoxyethyl phosphino ethane Uptake across myocardial membranes is passive and requires presence of intact electrochemical membrane gradients Binds to a low molecular weight protein fraction in the cytosol complex There is limited redistribution after initial uptake which would appear to limit its usefulness in determining viability

21 Myocardial Resting Dose Select agents for myocardium viability. Second reinjection may be needed. IV administration Tc-99m sestamibi adult doses 8-30 mci Tc-99m tetrofosmin adult doses 8-30 mci Tl-201 chloride adult doses 2-5 mci Tl-201 chloride redistributes 3-4 hours after injection.

22 Indications Detection and evaluation of CAD (coronary artery disease) Coronary bypass surgery or angioplasty Detection of viable tissue (Tl-201) Evaluation of MI, chest pain, SOB, family history of heart disease. Evaluation of blood work indicators ie: elevated creatine phosphokinase, troponin etc.

23 Myocardial Stress Dose Tc-99m sestamibi Tc99m tetrofosmin = mci Tl-201 chloride 3-5 mci IV administration. Must have patent line. Myocardial localization same as resting.

24 Indications Same as resting protocals. Contraindications : Chest pain Discontinue chemical stressors: Caffeine Persantine Viagra

25 Contraindications High blood pressure Not comfortable weaned from nitroglycerin Allergies to chemicals (stress pharmaceuticals) Lung conditions (asthmatic reaction to persantine or adenosine) dobutamine used in these cases.

26 Adenosine & Dipyridamole Pharmacologic Effect Immediate with Adenosine Delayed with Dipyridamole (Converted to Adenosine; Peak reached after stopped) Absolute Contraindications Asthmatics with persistent wheezing 2 nd or 3 rd degree AV block, sick sinus node (Unless pt has functioning pacemaker) Systolic BP < 90 mm Hg Dipyridamole use < 24hrs; Xanthines <12hrs

27 Pharmacologic Stress - Adenosine Adenosine START INFUSION Perfusion Radiopharmaceutical Adenosine END INFUSION START INFUSION END INFUSION Recommended Adult Dose: 140ug/kg/min x 6 mins Hemodynamic Effects Modest increase in heart rate Modest decrease in systolic & diastolic

28 Pharmacologic Stress- Dipyridamole Dipyridamole START INFUSION Dipyridamole END INFUSION INJECT PERFUSION AGENT OR OR Recommended Adult Dose:.142mg/kg/min x4 mins * No Added Benefit above 60 mg TOTAL Infusion Hemodynamic Effects Modest increase in heart rate Modest decrease in systolic & diastolic

29 Pharmacologic Effect Dobutamine Stimulates sympathetic nervous system β1 receptors and used when adenosine & dipyridamole contra-indicated Contraindications Recent MI or unstable angina Critical aortic stenosis, dissection or aneurysm Atrial tachyarrhythmia Prior history of ventricular tachycardia Uncontrolled hypertension

30 Pharmacologic Stress- Dobutamine START 5 ug/kg/min to 10 ug/kg/min Dobutamine to 20 ug/kg/min to 30 ug/kg/min to 40 ug/kg/min INJECT Perfusion Agt Dobutamine END INFUSION Recommended Adult Dose: 5-10ug/kg/min x3 mins * Increase at 3 min intervals to 20, 30, 40 Hemodynamic Effects Modest increase in heart rate (Beta blockers limit effect) Modest decrease in systolic & diastolic

31 Regulatory Food For Thought: Compounding Medications and JCAHO

32 Regadenoson Lexiscan is simple, single unit dose injection standardized for all patients, regardless of weight 8 out of 10 now use this agent

33 Cardiac PET Imaging Perfusion studies Rest-stress perfusion imaging Detection of coronary artery disease and assessing the progression of coronary artery disease Viability studies Perfusion-metabolism imaging Identification of tissue that may recover contractile function following revascularization techniques

34 Nitrogen-13 Ammonia PET Perfusion Agent Cyclotron Produced Synthesis < 30 mins Half-life = 10 mins Approved by CMS

Shallow metal half-cyclinders, later called dees after their shape, serve as electrodes Charged particles injected into the gap near the center are pulled by the potential into the electrode A The

35 Shallow metal half-cyclinders, later called dees after their shape, serve as electrodes Charged particles injected into the gap near the center are pulled by the potential into the electrode A The magnetic field, perpendicular to the plane of the cylinders, bends them in a semicircle back into the gap In the meantime the electric field has reversed and can pull them into electrode B, emerging again in step with the electric field, eventually spiraling out to the edge Each passage through the gap boosts the particles to higher energies.

36 Regulatory Food For Thought: PET Drugs and FDA

37 CardioGen-82 (Sr 82 / Rb 82 Generator) PET Perfusion Agent No cyclotron required Half life = 75 secs Long-lived Sr85 contaminant Distinguish normal from abnormal myocardium in suspected MI

38 Infusion System Schema

39 Regulatory Food For Thought: Generator Breakthrough and FDA

40 F-18 Flurpiridaz Longer half-life of F-18 vs N-13 Ammonia and Rb-82 would permit commercial distribution Eliminates need for on-site medical cyclotron or costly generator infusion system Phase III efforts demonstrated better target to background resolution vs Ammonia, over-reporting findings Therefore, required increase in cohort

distribution of the radiotracer in all myocardial regions J Am

41 Representative Normal F18Flurpiridaz A) Consecutive tomograms of paired stress (top row) and rest (bottom row) images show normal distribution of the radiotracer in all myocardial regions J Am Coll Cardiol Img. 2012;5(12): doi: /j.jcmg

3 coronary artery vascular territories associated with transient ischemic cavity

42 Representative Abnormal F18Flurpiridaz (B) Paired stress (top row) and rest (bottom row) images show extensive reversible regional perfusion defects in all 3 coronary artery vascular territories associated with transient ischemic cavity dilation. J Am Coll Cardiol Img. 2012;5(12): doi: /j.jcmg

43 Myocardial Viability Imaging Mechanism of Uptake & Metabolism Myocardial cells continuously utilize chemicals (K + analogs & nitrates) and substrates (free fatty acids & glucose) to meet energy needs Impact on Patient Management Early referral to revascularization improves Survival Left Ventricular function Heart failure symptoms & exercise capacity Reduces readmissions for CHF

44 Cardiac Viability (Done only at rest) Tl-201 SPECT study FDG PET study Ant Sep Inf Ant Lat Apex Inf Apex Sep Lat

45 Preparation for FDG Study Non-Diabetic Patients NPO for six hours Oral ( Glucola ) or IV glucose loading Diabetic Patients Oral glucose leads to sub-optimal images Modified Protocol for IV glucose loading Fasting BG < 125 mg/dl, give 25g 50% dextrose Fasting BG , give 13g 50% dextrose Fasting BG >225, give regular insulin # units = (BG 50) / 25 Inject FDG if BG < 150mg/dL

46 Perfusion & Metabolism Patterns Perfusion Glucose Metabolism Normal Non-Viable Viable

47 Paradigm Shift in Markers? Stenosis Ischemia Necrosis 1980 s: Myocyte Necrosis 1990 s: Cardiac Myocyte Necrosis 2000 s: Ischemia and Vessel Inflammation 1. Dx prior to cell death 2. Better outcomes 3. Efficient resource use 4. Risk stratification in the ED without need for cardiologists/radiologists

48 New Biochemical Markers Heart Type Fatty-Acid Binding Protein (H-FABP) Choline Serum Amyloid A Malondialdehyde-modified LDL Glutathione Peroxidase 1 Monocyte Chemoattractant Protein 1 (MCP-1) Ischemia Modified Albumin (IMA) Myeloperoxidase (MPO) CD 40 Ligand C-Reactive Protein (CRP) Pregnancy-Associated Plasma Protein A (PAPP-A) Placenta-derived Growth Factor (PDGF)

49 Let s Review

51 Thanks For Your Attention!

Get This Article! http://imaging.onlinejacc.org/article.aspx?articleid=1476546 Dilsizian V, Taillefer R.

52 Get This Article! Dilsizian V, Taillefer R. Journey in Evolution of Nuclear Cardiology: Will There Be Another Quantum Leap With the F- 18 Labeled Myocardial Perfusion Tracers?. J Am Coll Cardiol Img. 2012;5(12):

OTHER NON-CARDIAC USES OF Tc-99m CARDIAC AGENTS Tc-99m Sestamibi for parathyroid imaging, breast tumor imaging, and imaging of other malignant tumors.

OTHER NON-CARDIAC USES OF Tc-99m CARDIAC AGENTS Tc-99m Sestamibi for parathyroid imaging, breast tumor imaging, and imaging of other malignant tumors. DEFINITION OF CARDIAC RADIOPHARMACEUTICAL: A radioactive drug which, when administered for purpose of diagnosis of heart disease, typically elicits no physiological response from the patient. Even though